title: A quantum mechanics/molecular mechanics study of the protein-ligand interaction of two potent inhibitors of human O-GlcNAcase: PUGNAc and NAG-thiazoline.
abstract: O-glycoprotein 2-acetamino-2-deoxy-beta- d-glucopyranosidase ( O-GlcNAcase) hydrolyzes 2-acetamido-2-deoxy-beta- d-glucopyranose ( O-GlcNAc) residues of serine/threonine residues of modified proteins. O-GlcNAc is present in many intracellular proteins and appears to have a role in the etiology of several diseases including cancer, Alzheimer's disease, and type II diabetes. In this work, we have carried out molecular dynamics simulations using a hybrid quantum mechanics/molecular mechanics approach to determine the binding of two potent inhibitors, PUGNAc and NAG, with a bacterial O-GlcNAcase. The results of these simulations show that Asp-401, Asp-298, and Asp-297 residues play an important role in the protein-inhibitor interactions. These results might be useful to design compounds with more interesting inhibitory activity on the basis of its three-dimensional structure.
authors.affiliation: Laboratorio de Planejamento e Desenvolvimento de Farmacos, Instituto de Ciencias Exatas e Naturais, Universidade Federal do Para, CP 11101, 66075-110, Belem, PA, Brazil
authors.forename: Jeronimo
authors.initials: J
authors.lastname: Lameira
authors.forename: Cláudio Nahum
authors.initials: CN
authors.lastname: Alves
authors.forename: Vicent
authors.initials: V
authors.lastname: Moliner
authors.forename: Sergio
authors.initials: S
authors.lastname: Martí
authors.forename: Natalia
authors.initials: N
authors.lastname: Kanaan
authors.forename: Iñaki
authors.initials: I
authors.lastname: Tuñón
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D055162:Biocatalysis / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010091:Oximes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D048448:Phenylcarbamates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011522:Protons; D011789:Quantum Theory; D055672:Static Electricity; D013816:Thermodynamics; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D010091:Oximes; D048448:Phenylcarbamates; D011522:Protons; D013844:Thiazoles; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; C487818:N-acetylglucosamine thiazoline; D000117:Acetylglucosamine